1. Field of the Invention
The present invention relates to the preparation and use of amino-acyl-type and catecholamine-type hepatobiliary and cardiac contrast agents useful in magnetic resonance imaging. The contrast agents have multiple carboxyl groups to chelate a variety of metal (II) or (III) ions.
2. Description of Related Art
This invention relates to contrast agents for medical magnetic resonance imaging (MRI).
A contrast agent is an exogenous substance that either augments or suppresses the normal in vivo MRI signal, thereby yielding additional diagnostic information. The theory and applications of various types of contrast agents have been described in the literature (1,2). [The Arabic numbers in parentheses in this section refer to the articles cited in this section.]
The applications of a given MRI contrast agent are determined by its distribution in vivo. The mechanisms controlling the initial biodistribution can be classed as physico-chemical, i.e., dependent only upon such properties as molecular size, charge, lipophilicity, surface properties, etc.; or receptor-mediated, i.e., dependent upon the binding of a substrate to a specific receptor in or on cells. Different organs may handle the same contrast agent by different mechanisms. For example, the molecular size of the agent may result in its filtration by the kidneys (or confinement to the vascular space) while it is cleared by receptor-mediated transport in the liver.
Contrast agents exhibiting a physico-chemical distribution mechanism include the gadolinium (III) complex of diethylenetriaminepentaacetic acid (Gd-DTPA), which distributes in blood plasma and extracellular fluid, and albumin-(Gd-DTPA).sub.n, which remains largely intravascular (1,2). The former is used to demonstrate blood-brain barrier lesions or to reveal renal anatomy and function (3), while the latter has been used experimentally to delineate the vasculature (4) and determine brain blood volume (5,6). Iron-dextran, although a colloid, has a sufficiently long plasma half-life (12 hr) to be used as an intravascular T2 contrast agent (7), as do some superparamagnetic iron oxide particle preparations (8,9).
Because of its role in the removal of exogenous compounds from general circulation, the liver is able to actively take up and concentrate soluble, as well as particulate, contrast agents. The pathways followed by solutes from plasma to bile have been reviewed (10-11) and are diagrammed in FIG. 4. Passage into the hepatocyte across the cell membrane can take place by pinocytosis, passive diffusion, and/or by carrier-mediated systems that transport bile acids, bilirubin, organic anions, organic cations, neutral organic compounds, or inorganic ions. The substrate specificity of different carrier systems can partially overlap (e.g., organic anions and bile acids). The substrate may be metabolized intracellularly and/or conjugated with glucuronic acid or glutathione, for example. Finally, excretion into bile canaliculi again involves passage through a cell membrane. The mechanism of biliary excretion for a given compound may differ from that operative for its uptake.
The relative rates of metabolism, biliary elimination, and renal excretion determine the clearance of drugs and their metabolites from blood plasma and their persistence in any one organ system. However, presently the factors that direct one compound to be excreted in the bile and another in the urine are not completely understood. Molecular weight, polarity, and molecular structure in relation to binding to plasma and transporter proteins are important. There appears to be a general molecular weight threshold, which is species-dependent (ca. 300 for rats and 600 for humans) below which urinary excretion dominates (10-11). Hydrophilic-lipophilic balance appears to play a critical role in biliary excretion (10-11). However, a priori prediction is not presently possible.
The liver has provided the first example of receptor-mediated localization of an MR contrast agent--Fe-EHPG (EHPG is Ethylene-bis(hydroxyphenylglycine)) (12). Other iron (13-15), manganese (16-17), and gadolinium (18) chelates have since been described that have either potential for, or have demonstrated receptor-mediated hepatocyte uptake.
It has been reported by others that the anionic chelates Fe-EHPG, Fe-HBED (HBED=bis-(hydroxybenzyl)ethylenediaminediacetic acid), and Fe-PGDF (PGDF=N-3-(phenylglutaryl)desferrioxamine B) are transported in the liver by a system or systems inhibitable by BSP (bromosulfophthalein) (13,15).
The lipophilic chelate Gd-BOPTA ("benzyloxypropionic-tetraacetate," a derivative of DTPA) was shown to have significant biliary excretion (38.6% of injected dose in bile at 6 hr) (18). No information was reported on the mechanism of transport (e.g., passive diffusion or anionic transport) of this compound. Gd-BOPTA produced a larger signal enhancement (48%) in liver than Gd-DTPA (16%) in T1-weighted spin-echo images at 0.5 Tesla.
Additionally, other organs and tissues may possess receptors with affinity for certain classes of substrates, e.g., amino acids, peptides or catechol amines (19-24). These receptors may also bind molecules that resemble the substrate, e.g., a derivative of an amino acid that is present in a peptide substrate (22) or an amide derivative of a naturally occurring catechol amine such as dopamine. The contrast agents of this invention may in part localize by such a mechanism. Furthermore, the localization of the catechol containing contrast agent of the present invention may depend in part on their respective reduction-oxidation properties.
To date, magnetic resonance imaging (MRI) has played a minor role in imaging of the liver and abdomen of a human being because of degradation of image quality by motion artifacts, and by the lack of suitable contrast agents. Recent technical advances in instrumentation (e.g., self-shielded gradient coils) and pulse sequences (e.g., echo-planar and turbo-flash techniques) promise to alleviate the motion-related problems of the torso and abdomen, and make contrast agent development all the more important for continued progress in abdominal MRI.
General background in the use of MRI contrast agents and of their preparation and purification are described, for example, in:
H. Gries et al., U.S. Pat. No. 4,647,447; PA1 R. B. Lauffer et al., U.S. Pat. Nos. 4,899,755 and 4,880,008; PA1 B. L. Engelstad et al., U.S. Pat. No. 4,909,257; PA1 D. L. White et al., U.S. Pat. No. 4,999,445. PA1 wherein M is a metal (II) or (III) ion independently selected from the group consisting of metals of atomic number 21 to 31, metals of atomic number 39 to 50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82; and PA1 L.sup.1 is a polydentate amino-acyl-type chelating moiety of Formula 1: ##STR1## wherein Q, J, x, X' and Z are each independently selected from the group consisting of --CH.sub.2 --(C.dbd.O)OR.sup.1 and --CH.sub.2 --(C.dbd.O)--NH--CH(R) (A); PA1 wherein each R is independently selected from the group consisting of -hydrogen, --K, --W and --K--W, wherein each K is an alkyl group having 1-7 carbon atoms, and each W is independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and PA1 each A is a carbonyl-containing moiety independently selected from the group consisting of --(C=O)OR.sup.1 and --(C.dbd.O)--N(R.sup.2) (R.sup.3), wherein R.sup.1, R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen (i.e. the acid), alkyl having 1-7 carbon atoms, cyclohexyl, phenyl, benzyl, 1-naphthyl and 2-naphthyl, provided that when every A is --(C.dbd.O)OR.sup.1 and every R.sup.1 is hydrogen, then at least one R is --W or --K--W; and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1; PA1 or the pharmaceutically acceptable salt(s) thereof. PA1 (a) contacting a structure of the following formula: ##STR2## wherein D and E are CH.sub.2 (C.dbd.O)OR.sup.1, with an amino acid of the structure H.sub.2 N--CH(R)--(C.dbd.O)OH, an ester of the structure H.sub.2 N--CH(R)--(C.dbd.O)OR.sup.1 or an amide of the structure H.sub.2 N--CH(R)--(C.dbd.O)--N(R.sup.2) (R.sup.3); PA1 (b) removing the solvent and recovering the compound of Formula 1. PA1 (a) injecting the mammal with an amino-acyl-type contrast agent in a dose amount having a concentration of the complex L.sup.1 --M of between about 0.5 and 5000 micromol/kg of body weight of the mammal; PA1 (b) placing the mammal of step (a) in a magnetic field irradiating with radio-frequency energy such that nuclear magnetic resonance can be detected; and PA1 (c) analyzing the imaging nuclear magnetic resonance signals obtained. PA1 wherein M is a metal (II) or (III) ion independently selected from the group consisting of metals of atomic number 21 to 31, metals of atomic number 39 to 50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82; and PA1 L.sup.2 is a polydentate catecholamine-type chelating moiety of Formula 2: ##STR3## wherein G, T, V, V' and Y are each independently selected from the group consisting of --CH.sub.2 --(C.dbd.O)OR.sup.1 and --CH--(C.dbd.O)--NH--CH.sub.2 --R.sup.4 ; PA1 wherein each is independently selected from the group consisting of --CH.sub.2 -aryl, --CH.sub.2 CH.sub.2 -aryl, --CH.sub.2 -(substituted aryl), and --CH.sub.2 CH.sub.2 -(substituted aryl); and PA1 m is selected from 0, 1, 2 or 3, and PA1 n is selected from 0 or 1; PA1 or the pharmaceutically acceptable salt(s) thereof. PA1 (a) contacting a structure of the following formula: ##STR4## wherein D and E are CH.sub.2 (C.dbd.O)OR.sup.1, with a derivative of the structure NH.sub.2 --CH.sub.2 --R.sup.4 ; wherein R.sup.4 is independently selected from the group consisting of --CH.sub.2 -aryl, --CH.sub.2 CH.sub.2 -aryl, --CH.sub.2 -(substituted aryl), and --CH.sub.2 CH.sub.2 -(substituted aryl); and PA1 (b) removing the solvent and recovering the compound of Formula 2. PA1 (a) injecting the mammal with a catecholamine-type contrast agent in a dose amount having a concentration of the complex L.sup.2 --M of between about 0.5 and 5000 micromol/kg of body weight of the mammal; PA1 (b) placing the mammal of step (a) in a magnetic field irradiating with radio-frequency energy such that nuclear magnetic resonance can be detected; and PA1 (c) analyzing the imaging nuclear magnetic resonance signals obtained.
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All reference articles, patents, etc. cited in this application are incorporated herein by reference in their entirety.
It would be very useful to have organic chelate metal ion complexes which are specific for MRI imaging of the liver, the biliary tree, the upper small intestine, or the myocardial tissue. The present invention provides complexes and methods having these useful advantages.